Spermatozoa are matured and stored in the epididymis. Although knowledge of how this tissue is regulated during development and in the adult is growing, little is known about changes that take place within this tissue as males age. The aging Brown Norway rat offers the opportunity to study aging of the reproductive system without complexities consequent to simultaneous pathological changes. The long-term objective of this project is to understand the underlying mechanisms responsible for the change that occur in the epididymis as animals age. Our underlying hypothesis is that the adult epididymal epithelium exhibits cellular aging independently of the presence of spermatozoa in the luminal compartment and thus independently of a normally functioning testis. To test this hypothesis, four complementary approaches will be pursued. The first is to determine the cellular and physiological implication s of the morphological changes we have found in the epididymis during aging. Possible mechanisms which we will examine include increased oxidative stress, alterations in cell-cell interactions, and increased lysosomal activity. The second approach is to resolve how selective biochemical changes during aging are regulated; we will focus on the control of epididymal 5alpha-reductases and on proteins associated with apoptotic cell death. The third approach is to identify how aging affects the fertility and the functional characteristics of epididymal spermatozoa. In vivo fertility studies and in vitro insemination studies will be done; functional alterations in spermatozoa such as their decondensation pattern and DNA template functions will be assessed. The final approach is to determine how age associated changes are affected by endocrine and/or paracrine factors. Consequences of aging on the effect of orchidectomy and testosterone replacement, altered testicular input to the epididymis, and efferent duct ligation on epididymal structure and function will be studied. Together, these studies will not only provide specific knowledge about factors that cause this tissue to age, but may also provide new insight about the aging process of non-diving cells.